Isoindolinone compounds active as Kv1.5 blockers identified using a multicomponent reaction approach

Multicomponent reactions (MCRs): a useful access to the synthesis of benzo-fused γ-lactams

“…More recently, Shafiee et al [90] utilized propargylamine as the cycle-nitrogen delivering component and then submitted the obtained isoindolinones 44 (route A, Scheme 13) to an additional cyclization to furnish a pyrazinoisoindoledione derivative. Kajanus and co-workers [91] prepared eight isoindolinone derivatives 45 by this method with yields ranging from 32 to 79% (route B, Scheme 13).…”

A novel and highly stereoselective route for the synthesis of non-racemic 3-substituted isoindolin-1-one targets

“…3 Selected biological activities of other, related, 3-substituted isoindolin-1-one derivatives include affinity for 5-HT receptors, 4 as inhibitors of the MDM2-p53 protein-protein interaction, 5 and as Kv1.5 ion channel blockers. 6 Deprotonation and subsequent benzylic C-alkylation of the parent isoindolinone template has been previously explored as a route to such targets in racemic form. 7 This approach has been extended to include chiral auxiliary based approaches for the asymmetric synthesis of nonracemic 3-substituted isoindolin-1-ones: for example in Couture's application of an aminoprolinol-derived template, 8 Royer's use of phenylglycinol, 9 and Comins' approach using TCC esters for control of asymmetric alkylation.…”

Challenges Faced with Small Molecular Modulators of Potassium Current Channel Isoform Kv1.5

“…The compound 85 was well tolerated in rabbits with no signs of the CNS-like side effects observed for other Kv1.5 blockers (Figure 24). In 2016, Kajanus et al [102] synthesized multiple isoindolinone compounds as Kv1.5 blockers. The most potent compounds 88 and 89 exhibited an inhibitory effect with the IC50 values of 0.4 and 0.7 μM on Kv1.5, respectively.…”

“…Combination of the indazole with a cyclohexane-based template gave the most promising derivative 86 (Kv1.5 IC50: 138 nM) which demonstrated significant prolongation of AERP in the rabbit pharmacodynamic model (Figure 25). In 2016, Kajanus et al [102] synthesized multiple isoindolinone compounds as Kv1.5 blockers. The most potent compounds 88 and 89 exhibited an inhibitory effect with the IC50 values of 0.4 and 0.7 μM on Kv1.5, respectively.…”

“…SAR of 1-aryloxyethyl piperazine derivatives.In 2016, Kajanus et al[102] synthesized multiple isoindolinone compounds as Kv1.5 blockers. The most potent compounds 88 and 89 exhibited an inhibitory effect with the IC 50 values of 0.4 and 0.7 µM on Kv1.5, respectively.…”